Clinical trialPhase 3Bile duct and gallbladder cancer (biliary tract cancer)

Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study

Lancet Oncol · 2020185 patients in the primary analysis (124 ivosidenib, 61 placebo); 187 patients in the final overall survival analysis

Abou-Alfa GK, Macarulla T, Javle MM, et al. Lancet Oncol. 2020. 21:796-807

Study type: Clinical trial
Study name: ClarIDHy
Phase: Phase 3
Design: Randomised, double-blind, placebo-controlled trial in 49 hospitals in 6 countries; 2:1 randomisation (block size 6) stratified by number of previous regimens; crossover from placebo to ivosidenib allowed at radiological progression
Sample size: 185 patients in the primary analysis (124 ivosidenib, 61 placebo); 187 patients in the final overall survival analysis
Source: Lancet Oncol · 2020
Trial registration: NCT02989857

In plain words

People with advanced bile duct cancer (cholangiocarcinoma) with a change in the IDH1 gene, whose disease had grown after chemotherapy, took either ivosidenib tablets or a placebo. With ivosidenib the cancer grew later and the drug was well tolerated. Most patients in the placebo group later received ivosidenib; taking this into account, ivosidenib also helped patients live longer.

Key results

2.7 vs 1.4 months

Median progression-free survival (independent review)

HR 0.37 (95% CI 0.25–0.54); one-sided P below 0.0001

32% and 22%

6-month and 12-month progression-free survival with ivosidenib

No patient in the placebo group was progression free for 6 months or more

Median 10.3 vs 7.5 months

Overall survival, final analysis (intention to treat)

HR 0.79 (0.56–1.12); one-sided P=0.09; 43 patients crossed over (JAMA Oncol 2021)

Median 5.1 months with placebo

Overall survival adjusted for crossover (RPSFT)

HR 0.49 (0.34–0.70); one-sided P below 0.001

2% vs 0%

Objective response (independent review)

3 partial responses among 124 patients; stable disease 51% vs 28%

Dose and schedule cards

Ivosidenib (IDH1)

Previously treated, locally advanced or metastatic cholangiocarcinoma with an IDH1 mutationOn the page “Bile duct and gallbladder cancer (biliary tract cancer)” · After progression on first line: chemotherapy and targeted therapy

Previously treated, locally advanced or metastatic cholangiocarcinoma with an IDH1 mutation

Drug	Dose	Route	Schedule
Ivosidenib	500 mg once daily	Oral	Daily; not with a high-fat meal

Cycle length: Continuous (28-day cycles in ClarIDHy)
Duration: Until progression or unacceptable toxicity

Dose source: FDA label and ClarIDHy. With a strong CYP3A4 inhibitor: 250 mg. QTc above 480 to 500 ms: withhold and resume at 500 mg once 480 or less; above 500: withhold and resume at 250 mg. In cholangiocarcinoma, grade 3 toxicity: withhold until grade 1, then 500 mg; grade 4: 250 mg. Guillain–Barré syndrome: permanent discontinuation.

On the page “Bile duct and gallbladder cancer (biliary tract cancer)” · After progression on first line: chemotherapy and targeted therapy

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Ivosidenib (124 patients)

Oral ivosidenib 500 mg once daily in continuous 28-day cycles until progression or unacceptable toxicity; dose reduction to 250 mg was allowed to manage adverse events.

2Placebo (61 patients)

Matched placebo once daily in 28-day cycles; at radiological progression (investigator assessment), crossover to open-label ivosidenib was allowed (35 patients by the primary analysis and 43 by the final analysis).

Source of the regimen details: Full text of the Lancet Oncol 2020 paper (PMC7523268) and the FDA label for Tibsovo

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Patients aged 18 or older with histologically confirmed advanced (unresectable or metastatic) IDH1-mutant cholangiocarcinoma (mutation confirmed centrally by next-generation sequencing), with progression after previous therapy and up to 2 previous regimens for advanced disease (one gemcitabine-based or fluorouracil-based; no previous IDH inhibitor), ECOG 0 or 1, measurable disease by RECIST 1.1, life expectancy of at least 3 months and adequate haematological, hepatic and renal function. Active cardiac disease within 6 months, active hepatitis B or C infection and HIV were exclusion criteria.

Endpoints

Primary endpoint: progression-free survival by independent central review. Secondary endpoints: overall survival, objective response (RECIST 1.1), duration of and time to response, investigator-assessed progression-free survival, pharmacokinetics and pharmacodynamics, quality of life (EORTC QLQ-C30 and QLQ-BIL21) and EQ-5D-5L.

Safety and side effects

The most common grade 3 or worse adverse event in both groups was ascites (9 [7%] of 121 patients on ivosidenib and 4 [7%] of 59 on placebo). Serious adverse events were reported in 36 (30%) patients on ivosidenib and 13 (22%) on placebo. Adverse events led to dose reduction in 3% and to discontinuation in 6% (vs 8% with placebo), and there were no treatment-related deaths. In the final analysis, grade 3 or worse ascites occurred in 9% vs 7%, serious ivosidenib-related adverse events in 2%, and quality of life showed no apparent decline compared with placebo.

Clinical significance and place in guidelines

ClarIDHy was the first successful phase 3 trial of a targeted drug in cholangiocarcinoma and led to FDA approval of ivosidenib for previously treated IDH1-mutant cholangiocarcinoma. ESMO 2023 recommends it after at least one line of therapy [I, A], and the result made molecular testing of the tumour part of standard care.

Limitations

The absolute gain in median progression-free survival was small (2.7 vs 1.4 months) and the objective response rate only 2%. Overall survival in the intention-to-treat analysis was not significant because of extensive crossover from placebo, and the survival benefit rests on crossover adjustment (RPSFT), which assumes the treatment effect is the same whenever treatment is given.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.